The pathogenesis of IgA nephropathy, the most common form of glomerulonephritis in the world, is still largely unknown. The relationship between glomerular IgA deposits and development of renal lesions that precipitate in renal failure, have not been elucidated. On the basis of experimental and clinical observations we hypothesize that in glomerular IgA deposits the structure of IgA and the complexed antigen (IgA-IC) activate glomerular responses that trigger leukocytic infiltration. Proinflammatory cytokines from infiltrating cells induce or augment the generation of growth factors. The interplay of synergistic and antagonistic elements within this network alter the composition and production of the extracellular matrix that consummates in glomerular sclerosis, interstitial fibrosis, and renal failure. A comprehensive human IgA-mediated nephropathy experimental model will be developed in a T and B lymphocytes-deficient, Recombination Activation Gene-disrupted (knockout), mice. This model will provide a framework for elucidating in vivo the cellular and molecular mechanisms that are associated with glomerular human IgA immune deposits. To develop the model and evaluate the hypothesis, the following specific aims will be addressed: 1. We will construct human IgA1 and IgA2 as antigen-specific chimeric antibodies for formation of human IgA immune complexes. 2. We will elucidate the primary mechanisms that lead to human IgA-IC glomerular localization. 3. We will identify the mediators of glomerular responses to human IgA-IC by examining:complement deposition, procoagulant activation, phenotypic and genotypic expression of Selectins, and chemokines. 4. We will determine the nephritogenic profile of proinflammatory cytokines and growth factors in renal tissues with IgA immune deposits. 5. We will characterize in a chronic model of human IgA nephropathy the differential expression of extracellular matrix genes involved in the progressive stages of fibrosis associated with renal failure. These studies will provide an insight into cellular and molecular mechanisms underlying the pathogenesis of IgA nephropathy that can be targeted for development of therapy and prevention of progression to renal failure.